Needleless syringe

ABSTRACT

A method of distributing particles in a flow of gas and a needleless syringe for use in the needleless injection of particles into the skin or mucosa of a vertebrate subject are disclosed. The syringe includes a convergence which reduces pressure of the gas flowing in the gas flow path due to the Venturi effect such that particles initially located outside of the gas flow path are drawn into the gas flow path under the action of the reduced pressure and become entrained in the gas. An exit nozzle accelerates the particles so entrained. In another aspect of the invention, there is provided a method of creating a gas flow in a needleless syringe which comprises flowing gas through a first convergence into a chamber to form a transsonic gas jet in the chamber and passing the gas jet from the chamber into a second convergence and along the nozzle.

TECHNICAL FIELD

This invention relates to needleless syringes for use in deliveringparticles into target tissue of a subject, for example skin or mucosa.Said particles may, for example, comprise a drug, vaccine, diagnosticagent or carrier particle coated with a genetic material (or anycombination thereof).

BACKGROUND OF THE INVENTION

The ability to deliver pharmaceuticals through skin surfaces(transdermal delivery) provides many advantages over oral or parenteraldelivery techniques. In particular, transdermal delivery provides asafe, convenient and noninvasive alternative to traditional drugadministration systems, conveniently avoiding the major problemsassociated with oral delivery (e.g. variable rates of absorption andmetabolism, gastrointestinal irritation and/or bitter or unpleasant drugtastes) or parenteral delivery (e.g. needle pain, the risk ofintroducing infection to treated individuals, the risk of contaminationor infection of health care workers caused by accidental needle-sticksand the disposal of used needles). In addition, transdermal deliveryaffords a high degree of control over blood concentrations ofadministered pharmaceuticals.

A novel transdermal drug delivery system that entails the use of aneedleless syringe to fire powders (i.e. solid drug-containingparticles) in controlled doses into and through intact skin has beendescribed. In particular, U.S. Pat. No. 5,630,796 to Bellhouse et al.describes a needleless syringe that delivers pharmaceutical particlesentrained in a supersonic gas flow. The needleless syringe is used fortransdermal delivery of powdered drug compounds and compositions, fordelivery of genetic material into living cells (e.g. gene therapy) andfor the delivery of biopharmaceuticals to skin, muscle, blood or lymph.The needleless syringe can also be used in conjunction with surgery todeliver drugs and biologics to organ surfaces, solid tumours and/or tosurgical cavities (e.g. tumour beds or cavities after tumour resection).In theory, practically any pharmaceutical agent that can be prepared ina substantially solid, particulate form can be safely and easilydelivered using such devices.

One needleless syringe described in U.S. Pat. No. 5,630,796 comprises anelongate tubular converging-diverging nozzle having a rupturablemembrane initially closing the passage through the nozzle and arrangedsubstantially adjacent to the upstream end of the nozzle. Particles of atherapeutic agent to be delivered are disposed adjacent to therupturable membrane and are delivered using an energizing means whichapplies a gaseous pressure to the upstream side of the membranesufficient to burst the membrane and produce a supersonic gas flow(containing the pharmaceutical particles) through the nozzle fordelivery from the downstream end thereof. The particles can thus bedelivered from the needleless syringe at very high velocities which arereadily obtainable upon the bursting of the rupturable membrane. Thepassage through the nozzle has an upstream convergent portion, leadingthrough a throat to a downstream, divergent portion. Theconverging-diverging passage is used to accelerate the gas to supersonicspeed. The gas is first brought to Mach 1 in the throat and thedownstream divergence accelerates it to a steady state supersonic speed.

With the syringes described in U.S. Pat. No. 5,630,796 particles can bedelivered at a large range of velocities with potentially non-uniformspatial distribution across the target surface. A variation in particlevelocity can make it difficult to deliver high-potency powdered drugs,vaccines etc to specific target layers within the skin. Furthermore,non-uniform spatial distribution can cause problems which would beameliorated if a more even spatial distribution could be achieved. Inaddition, flow considerations inside the syringes can limit the maximumsize of the target area on the target tissue over which the particlesmay be spread, limiting the maximum particle payload size.

Additionally, with the syringes described in U.S. Pat. No. 5,630,796 thebursting of the rupturable membrane can make operation of the syringefairly noisy, which can be a disadvantage when treating small childrenfor example.

It would be advantageous to have a needless syringe which operatesquietly and in which the particles may be spread over a larger targetarea, with a reasonably uniform distribution over that target area. Byspreading the particles of the payload over a larger target area, withgood uniformity of particle distribution over that target area, largerpayloads may be delivered.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention there is provided amethod of distributing particles in a flow of gas from a needlelesssyringe, the method comprising:

(a) flowing gas through a first convergence in a gas flow path withinthe syringe thereby expanding the gas and reducing its pressure toprovide a region of reduced gas pressure;

(b) utilizing said reduced gas pressure to draw a payload of particlesinto said gas flow path from outside of said gas flow path and toentrain them in the gas flow in said gas flow path; and

(c) directing the gas through a delivery nozzle bounding said gas flowpath so as to accelerate the entrained particles and cause the entrainedparticles to be distributed across substantially the full width of thenozzle at the nozzle's downstream exit.

By distributing the particles in the flow of gas from a needlelesssyringe using the method of the above first aspect of the presentinvention, whilst the nozzle's downstream exit is positioned adjacent atarget area of skin or mucosa, the particles may be administered to theskin or mucosa.

According to a second aspect of the present invention there is provideda needleless syringe for use in the needleless injection of particlesinto the tissue of a vertebrate subject, the syringe comprising:

-   -   a gas flow path arranged to receive gas from a gas source;    -   a first convergence in said gas flow path for reducing the        pressure of the gas flowing through said gas flow path;    -   a particle inlet in communication with said gas flow path        downstream of at least the start of said first convergence that        allows a payload of particles to be drawn into the gas flow path        via the inlet under the action of reduced pressure gas to become        entrained in the gas; and    -   a gas/particle exit nozzle bounding said gas flow path for the        acceleration therealong of the drawn in particles entrained in        the gas.

The use of a reduced pressure to draw particles into the gas flow pathallows the membranes which were previously used to retain the particlesto be dispensed with. This in turn ensures that the device works morequietly since the noise created by the bursting of the membrane is nolonger present.

Preferably, the device is so constructed and arranged that substantialboundary layer separation between the wall of the nozzle and the gas jetis avoided thus enabling the particles accelerated out of the exitnozzle in the gas jet to be distributed across substantially the fullwidth of the nozzle's downstream exit.

By avoiding substantial boundary layer separation of the gas jet fromthe nozzle wall, the particles being accelerated can be distributedacross substantially the full cross-section of the nozzle at thenozzle's downstream exit. Where the nozzle has a divergent downstreamsection, it has been found that by extending the length of the nozzle toincrease the diameter of the nozzle at its downstream exit,significantly larger target areas on the skin or mucosa may bepenetrated by the particles, with good uniformity of distribution acrossthe larger target area.

According to a third aspect of the present invention there is provided amethod of creating a gas flow in a needleless syringe, said methodcomprising:

-   -   flowing gas through a first convergence into a chamber of        increased cross-section to form a transsonic gas jet in said        chamber;    -   passing the gas jet from the chamber through a second        convergence into and along a nozzle.

The use of two convergences in this manner has been found to be aparticularly advantageous way of creating a gas flow field suitable foraccelerating particles in a needleless syringe.

BRIEF DESCRIPTION OF THE FIGURES

Embodiments of apparatus in accordance with the present invention willnow be described, by way of example only, with reference to theaccompanying drawings, in which:

FIG. 1 is a schematic cross-section along the central longitudinal axisof the downstream end of a first embodiment of a needleless syringe;

FIG. 2 is an axial cross-section taken along the line II-II in FIG. 1;

FIG. 3 is a schematic cross-section along the central longitudinal axisof a needleless syringe of the first embodiment of the invention,showing a push-button gas cylinder.

FIG. 4 is a top plan view of the target area of a gel target after thefiring at it of particles from the first embodiment of syringe;

FIG. 5 is an enlarged cross-section through the gel target of FIG. 4,showing particle distribution across and penetration into the target;

FIG. 6 is a schematic cross-section along the central longitudinal axisof the downstream end of a second embodiment of a needleless syringe.

FIG. 7 is a top plan view of the target area of a gel target after thefiring at it of a 1 mg payload of particles from the second embodimentof a syringe;

FIG. 8 is an enlarged cross-section through part of the gel target ofFIG. 7, showing particle distribution across and penetration into thetarget;

FIG. 9 is an enlarged cross-section through the full diametral width ofthe gel target of FIG. 7;

FIG. 10 is a top plan view of the target area of a gel target after thefiring at it of a 2 mg payload of particles from the second embodimentof the syringe;

FIG. 11 is an enlarged cross-section through part of the gel target ofFIG. 10;

FIG. 12 is a top plan view of the target area of a gel target after thefiring at it of a 3 mg payload of particles from the second embodimentof the syringe;

FIG. 13 is an enlarged cross-section through part of the gel target ofFIG. 12;

FIG. 14 is a schematic cross-section along the central longitudinal axisof a needleless syringe according to a third embodiment of the presentinvention, showing an alternative geometry of first convergence;

FIG. 15 is a schematic cross-section along the central longitudinal axisof a needleless syringe according to a fourth embodiment of the presentinvention showing a divergent section instead of a particle entrainmentchamber;

FIG. 16 is a cross-section along the central longitudinal axis of afifth embodiment of a needleless syringe;

FIG. 17 is a schematic cross-section, on an enlarged scale, along thecentral longitudinal axis of a disposable drug cassette suitable for usewith a needleless syringe;

FIGS. 18 a to 18 f show views of a particle cassette and plugarrangement according to the present invention;

FIG. 19 is a schematic cross-section along the central longitudinal axisof a needleless syringe showing a particle cassette and gas cannister inplace;

FIG. 20 is a view similar to FIG. 19, but with a different nozzlesection that incorporates a divergence;

FIG. 21 is a view similar to that of FIGS. 19 and 20, except that thenozzle comprises a parallel sided extension section;

FIG. 22 is a schematic cross-section across the central longitudinalaxis of a needleless syringe in accordance with a sixth embodiment ofthe present invention, showing a novel actuating lever;

FIG. 23 is a schematic cross-section along the central longitudinal axisof the downstream end of a needleless syringe according to a seventhembodiment of the present invention, showing a configuration forinjecting the particles into the flow stream;

FIG. 24 is a schematic cross-section along the central longitudinal axisof the downstream end of a needleless syringe according to an eighthembodiment of the present invention, showing a configuration forpreventing boundary layer separation of the jet;

FIG. 25 is a schematic cross-section along the central longitudinal axisof the downstream end of a needleless syringe according to a ninthembodiment of the present invention, showing an alternative nozzlegeometry referred to as a “fast expand” nozzle;

FIG. 26 shows a top plan view of the target area of a gel target, a sidecross-sectional view of the target and an enlarged side cross-sectionalview of the gel target after the firing at it of particles from thesyringe of FIG. 20;

FIG. 27 is a schematic cross-section along the central longitudinal axisof a needleless syringe, showing a silencer arrangement arranged aroundthe exit nozzle;

FIG. 28 is a top plan view of the target area of the gel target, a sidecross-sectional view through the gel target and an enlarged sidecross-sectional view through the gel target after the firing at it ofparticles from the syringe shown in FIG. 27;

FIG. 29 is a top plan view of the target area of the gel target, a sidecross-sectional view through the gel target and an enlarged sidecross-sectional view through the gel target after the firing at it ofparticles from the syringe shown in FIG. 21;

FIG. 30 is a top plan view of the target area of the gel target, a sidecross-sectional view through the gel target and a graph showing thepenetration depth variation with position after the firing at the geltarget of particles from the needleless syringe shown in FIG. 20;

FIG. 31 is a top plan view of the target area of the gel target, a sidecross-sectional view through the gel target and a graph showing thepenetration depth variation with position after the firing at the geltarget of particles from the needleless syringe shown in FIG. 21;

FIG. 32 is a top plan view of the target area of the gel target, a sidecross-sectional view through the gel target and a graph showing thepenetration depth variation with position after the firing at the geltarget of particles from the needleless syringe shown in FIG. 21;

FIG. 33 is a top plan view of the target area of the gel target, a sidecross-sectional view through the gel target and an enlarged sidecross-sectional view through the gel target respectively, after thefiring at it of particles from the syringe shown in FIG. 21; and

FIG. 34 is a top plan view of the target area of a gel target, a sidecross-sectional view through the gel target and an enlarged sidecross-sectional view through the gel target after the firing at it ofparticles from the syringe shown in FIG. 20.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularpharmaceutical formulations or process parameters as such may, ofcourse, vary. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments of theinvention only, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a therapeutic agent” includes a mixture of two or moresuch agents, reference to “a gas” includes mixtures of two or moregases, and the like.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains.

The following terms are intended to be defined as indicated below.

The term “needleless syringe,” as used herein, expressly refers to aparticle delivery system that can be used to deliver particles intoand/or across tissue, wherein the particles may have an average sizeranging from about 0.1 to 250 μm, preferably about 1-70 μm, morepreferably 10-70 μm. Particles larger than about 250 μm can also bedelivered from these devices, with the upper limitation being the pointat which the size of the particles would cause untoward pain and/ordamage to the target tissue. The particles may be delivered at highvelocity, for example at velocities of at least about 150 m/s or more,and more typically at velocities of about 250-300 m/s or greater. Suchneedleless syringes were first described in commonly-owned U.S. Pat. No.5,630,796 to Bellhouse et al., incorporated herein by reference, andhave since been described in commonly owned International PublicationNos. WO 96/04947, WO 96/12513, and WO 96/20022, all of whichpublications are also incorporated herein by reference. These devicescan be used in the transdermal delivery of a therapeutic agent intotarget skin or mucosal tissue, either in vitro or in vivo (in situ); orthe devices can be used in the transdermal delivery of generally inertparticles for the purpose of non- or minimally invasive sampling of ananalyte from a biological system. Since the term only relates to deviceswhich are suitable for delivery of particulate materials, devices suchas liquid-jet injectors are expressly excluded from the definition of a“needleless syringe.”

The term “transdermal” delivery captures intradermal, transdermal (or“percutaneous”) and transmucosal administration, i.e., delivery bypassage of a therapeutic agent into and/or through skin or mucosaltissue. See, e.g., Transdermal Drug Delivery: Developmental Issues andResearch Initiatives, Hadgraft and Guy (eds.), Marcel Dekker, Inc.,(1989); Controlled Drug Delivery: Fundamentals and Applications,Robinson and Lee (eds.), Marcel Dekker Inc., (1987); and TransdermalDelivery of Drugs, Vols. 1-3, Kydonieus and Berner (eds.), CRC Press,(1987). Aspects of the invention which are described herein in thecontext of “transdermal” delivery, unless otherwise specified, are meantto apply to intradermal, transdermal and transmucosal delivery. That is,the present invention, unless explicitly stated otherwise, should bepresumed to be equally applicable to intradermal, transdermal andtransmucosal modes of delivery.

As used herein, the terms “therapeutic agent” and/or “particles of atherapeutic agent” intend any compound or composition of matter which,when administered to an organism (human or animal) induces a desiredpharmacologic, immunogenic, and/or physiologic effect by local and/orsystemic action. The term therefore encompasses those compounds orchemicals traditionally regarded as drugs, vaccines, andbiopharmaceuticals including molecules such as proteins, peptides,hormones, biological response modifiers, nucleic acids, gene constructsand the like. More particularly, the term “therapeutic agent” includescompounds or compositions for use in all of the major therapeutic areasincluding, but not limited to, adjuvants, anti-infectives such asantibiotics and antiviral agents; analgesics and analgesic combinations;local and general anesthetics; anorexics; antiarthritics; antiasthmaticagents; anticonvulsants; antidepressants; antigens, antihistamines;anti-inflammatory agents; antinauseants; antineoplastics; antipruritics;antipsychotics; antipyretics; antispasmodics; cardiovascularpreparations (including calcium channel blockers, beta-blockers,beta-agonists and antiarrythmics); antihypertensives; diuretics;vasodilators; central nervous system stimulants; cough and coldpreparations; decongestants; diagnostics; hormones; bone growthstimulants and bone resorption inhibitors; immunosuppressives; musclerelaxants; psychostimulants; sedatives; tranquilizers; proteins peptidesand fragments thereof (whether naturally occurring, chemicallysynthesized or recombinantly produced); and nucleic acid molecules(polymeric forms of two or more nucleotides, either ribonucleotides(RNA) or deoxyribonucleotides (DNA) including both double- andsingle-stranded molecules, gene constructs, expression vectors,antisense molecules and the like).

Particles of a therapeutic agent, alone or in combination with otherdrugs or agents, are typically prepared as pharmaceutical compositionswhich can contain one or more added materials such as carriers,vehicles, and/or excipients. “Carriers,” “vehicles” and “excipients”generally refer to substantially inert materials which are nontoxic anddo not interact with other components of the composition in adeleterious manner. These materials can be used to increase the amountof solids in particulate pharmaceutical compositions. Examples ofsuitable carriers include water, silicone, gelatin, waxes, and likematerials. Examples of normally employed “excipients,” includepharmaceutical grades of dextrose, sucrose, lactose, trehalose,mannitol, sorbitol, inositol, dextran, starch, cellulose, sodium orcalcium phosphates, calcium sulfate, citric acid, tartaric acid,glycine, high molecular weight polyethylene glycols (PEG), andcombinations thereof. In addition, it may be desirable to include acharged lipid and/or detergent in the pharmaceutical compositions. Suchmaterials can be used as stabilizers, anti-oxidants, or used to reducethe possibility of local irritation at the site of administration.Suitable charged lipids include, without limitation,phosphatidylcholines (lecithin), and the like. Detergents will typicallybe a nonionic, anionic, cationic or amphoteric surfactant. Examples ofsuitable surfactants include, for example, Tergitol® and Triton®surfactants (Union Carbide Chemicals and Plastics, Danbury, Conn.),polyoxyethylenesorbitans, e.g., TWEEN® surfactants (Atlas ChemicalIndustries, Wilmington, Del.), polyoxyethylene ethers, e.g., Brij,pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate andsalts thereof (SDS), and like materials.

The term “analyte” is used herein in its broadest sense to denote anyspecific substance or component that one desires to detect and/ormeasure in a physical, chemical, biochemical, electrochemical,photochemical, spectrophotometric, polarimetric, colorimetric, orradiometric analysis. A detectable signal can be obtained, eitherdirectly or indirectly, from such a material. In some applications, theanalyte is a physiological analyte of interest (e.g., a physiologicallyactive material), for example glucose, or a chemical that has aphysiological action, for example a drug or pharmacological agent.

As used herein, the term “sampling” means extraction of a substance,typically an analyte, from any biological system across a membrane,generally across skin or tissue.

First Embodiment

FIG. 1 is a schematic cross-section along the central longitudinal axisof the downstream end of a first embodiment of needless syringe inaccordance with the present invention. For reasons of clarity the gassource has been omitted. A possible gas source arrangement will bedescribed later in conjunction with FIGS. 3, 16 and 19-22.

In FIG. 1 the main body 1 of the syringe has a central apertureextending therethrough to form a lumen which bounds the gas flow paththrough the syringe, into the downstream end of which is fitted a nozzle2. As can be seen, the bore 3 of the nozzle is substantiallyparallel-sided, apart from a short taper at its upstream end.

Fitted generally midway along the central aperture of the main body 1 isa sonic nozzle 4. This sonic nozzle 4 is provided with an aperture whichforms a first convergence or constriction 5 to the flow of gas throughthe main body 1. In this embodiment, the first convergence takes theform of two successive fairly abrupt constrictions 5 a, 5 b. Theaperture of the first convergence is coaxial with the centrallongitudinal axis of the bore 3 of the nozzle 2.

The portion of the sonic nozzle 4 forming the downstream end of theconstriction 5 b projects outwardly (in a downstream direction) from theflat main downstream face 6 of the sonic nozzle 4. Although not shown,the sonic nozzle 4 may be held in place within the central aperture ofthe main body 1 by cooperating screwthreads, or an interference fit incombination with a downstream shoulder formed by the main body 1.

It will be noted that the flat, main downstream face 6 of the sonicnozzle 4 is spaced upstream from the upstream face 7 of nozzle 2. Thetwo faces 6, 7, in combination with the central aperture of the mainbody 1 between those two faces 6, 7, define a chamber 8 for particleentrainment.

The upstream end of the nozzle 2 forms a second convergence orconstriction 9 to the flow of gas through the main body 1. Again, inthis embodiment, this convergence 9 is a fairly abrupt constriction. Thenozzle 2 bounds the gas flow path, that is to say it surrounds anddefines the space through which the gas may flow.

The sonic nozzle constriction 5 b has a significantly reduced flowcross-section relative to the flow cross-section of the particleentrainment chamber 8. Similarly, the second convergence 9 has a muchreduced flow cross-section relative to the flow cross-section of thechamber 8. In the illustrated embodiment, the nozzle 2 is 50 mm inlength, the diameter of the sonic nozzle constriction 5 b is 1 mm andthe diameter of the exit nozzle constriction 9 is 2.3 mm. In contrast,the diameter of the particle entrainment chamber 8 is 5 mm.Consequently, the flow cross-section of the second convergence 9 isapproximately 5.3 times larger than the flow cross-section of the firstconvergence 5. The ratio of flow cross-sections between the first andsecond convergences 5, 9 is relevant to the functioning of the syringe.

A particle inlet in the form of a particle inlet passage 10 is providedextending radially through the main body 1. The radially innermost endof the particle inlet passage 10 opens into the particle entrainmentchamber 8 and the radially outer end of the passage 10 is arranged tocommunicate with a particle source 11 containing a payload of particles.

As can be seen from FIG. 1, the downstream tip of the sonic nozzle 4defining the first convergence 5 (in turn comprising constrictions 5 aand 5 b), is generally coincident with the central longitudinal axis ofthe particle inlet passage 10. It is thought that this relativepositioning is relevant if, as is described below, particles are to bedrawn into the particle entrainment chamber 8 as a result of thecreation of a reduced (sub-atmospheric in this embodiment) pressureregion within the chamber 8. If the particle inlet passage 10 is incommunication with a portion of the particle entrainment chamber 8 thatis at atmospheric pressure or higher, particles will not be drawn intothe particle entrainment chamber 8 when the syringe is fired, assumingthe particle source is at atmospheric pressure.

In the embodiment illustrated in FIG. 1, the particle source 11 takesthe form of a removable cassette having a central reservoir 12 in whichthe payload of particles (not shown) is deposited. When the cassette isengaged in a recess provided in the exterior side wall of the main body1, for example to form an interference fit therewith, a hole in thecassette provided at the base of the reservoir 12 lines up incommunication with the particle inlet passage 10. The top of thereservoir 12 is open to atmosphere.

In order to operate the syringe illustrated in FIGS. 1 and 2, a gassource is necessary to pressurize the central aperture of the main body1 upstream of the sonic nozzle 4 (ie. to the left of the sonic nozzle 4as drawn in FIG. 1). This gas source may take the form of a gas canisterlinked to a button cylinder (not shown), with operation of the buttoncylinder releasing a fixed amount of gas (for example 5 ml), enablingthe gas source to be used to deliver sequentially a plurality ofdiscrete payloads of particles without needing to be recharged.Alternatively, a closed gas cylinder containing a single dose of gassufficient for a single needleless injection may be provided. This lastarrangement is preferred as will be discussed below. The preferred gasfor the gas source is helium, with the gas cylinder containing heliumgas at a pressure of between 15 and 35 bar, preferably around 30 bar.The preferred driver gas is helium because it gives much higher gasvelocity than air, nitrogen or CO₂. The use of CO₂ as a source of drivergas is, however, superficially very attractive. Because, however, of thelarge variation of the saturation pressure of CO₂ with temperature, andthe much lower velocities achievable therewith, the use of CO₂ may belimited. A single-shot button canister 61 comprising a plunger 64 and asleeve body 62 defining a gas reservoir space 63 is shown attached tothe FIG. 1 syringe in FIG. 3.

In use, in order to operate the needleless syringe, a known volume ofgas at a known pressure is suddenly released from the gas source (notshown) into the central aperture of the main body to the upstream sideof the sonic nozzle 4. The initial pressure is sufficiently high so asto establish choked flow of the gas at the exit of the sonic nozzle 4,at its smallest constriction 5 b. The transsonic gas jet which issuesfrom the constriction 5 b into the particle entrainment chamber 8expands to create a reduced pressure region in the particle entrainmentchamber 8, in a manner similar to the venturi effect. The reducedpressure region is sub-atmospheric in this embodiment. It is thissub-atmospheric pressure region in cooperation with the atmosphericpressure in the particle source 11, which draws a payload of particlesfrom the reservoir 12 of the particle source 11 into the chamber 8,along the particle inlet passage 10, and in so doing causes the drawn-inparticles to become mixed and entrained in the expanding gas jet in theparticle entrainment chamber 8.

As with all embodiments, helium is preferably used as the driver gas.However, the gas issuing from the device is actually a mixture of heliumand air, due to the air that is drawn in along with the particles viathe particle inlet passage 10. Typically, the gas comprises about 15%air (by mass) at exit (the rest being helium).

The relative sizes of the first and second convergences 5,9, as well asthe longitudinal spacing therebetween, is such as to encourage theexpanding, diverging gas jet to attach to the walls of the secondconvergence 9 and to remain attached to the walls of the nozzle 2 as thejet passes down the bore 3 of the nozzle 2. The radius of the chamber 8is not thought to be particularly important although it should be largeenough so that a free jet is capable of being formed in the chamber. Byremaining attached, and thus avoiding substantial boundary layerseparation of the gas jet from the walls of the second convergence 9 andthe nozzle bore 3, the particles entrained in the gas jet aredistributed across substantially the full cross-section of the nozzlebore 3. In this way, when the gas jet, with particles entrained therein,exits the nozzle's downstream exit and impacts a target area of tissue(eg. skin or mucosa) positioned in close proximity to the nozzle exit,the size of the target area impacted by the particles will be generallyequal to the size of the bore 3 at the downstream exit of the nozzle 2and the particles will be well distributed across the target area. Byavoiding the formation of a substantial concentration of the particleswithin the core of the target area with no or few particles around theboundary of the target area, increased payloads of particles may bedelivered without the central core of the target area becomingoverloaded with particles.

Example of Performance of First Embodiment

When a syringe similar to that illustrated in FIGS. 1 and 2 was operatedwith a 5 ml button cylinder, (shown in FIG. 3) filled with air at apressure of approximately 30 bar, and using a 1.0 to 1.5 mg payload of55 μm lidocaine powder, the syringe was able to deliver the payload insuch a way as to consistently anaesthetise a 2 to 3 mm diameter of theforearm within one minute. Given that the diameter of the nozzle bore 3at the exit was 2.3 mm, the good spread of the particles across a targetarea substantially equal to the area of the nozzle bore 3 at the nozzleexit 2 will be appreciated.

Comparable performance was achieved with a canister containing helium ata pressure of 20 bar. When used with the 2.3 mm nozzle bore exitdiameter syringe illustrated in FIGS. 1 and 2, satisfactory anaesthesiawas obtained. Helium driver gas is in any event preferred to air as itgives more consistent behavior.

Performance comparisons (of which more later) between the differentembodiments were made by discharging the embodiment of device, loadedwith a known payload (between 1 mg and 3 mg) of 48 μm diameterpolystyrene spheres above a 3% agar gel target. Vented spacers werefitted to the end of the device nozzle so as to keep the devices at afixed distance from the target surface and at right angles to it. Afterfiring off the syringe the agar was then photographed to record thedelivery footprint. The gel target was then sliced across its diameterand thin sections were photographed through a microscope to establishthe depth of penetration of the individual particles.

FIGS. 4 and 5 show the footprint and penetration near the center of thetarget of polystyrene spheres delivered from the first embodiment ofdevice, at the conditions found to provide anaesthesia with lidocaine(ie. 3 ml cylinder filled with helium to 20 bar). The footprint diameterwas 3 mm and the maximum depth of particle penetration was about 180 μm.

Second Embodiment

Although the anaesthetic performance of the FIGS. 1 and 2 device wasrapid and effective, because of the generally parallel-sided nature ofthe bore 3 in the nozzle 2 the target area on the target tissue wasstill fairly small (of the order of 3 mm diameter).

FIG. 6 shows a second embodiment of a syringe in which the nozzle,instead of having a substantially parallel-sided bore, has a distinctdivergence. In FIG. 6, components similar to components in FIGS. 1 and 2have been given the same reference numerals. The reference numeralsassociated with the nozzle have, however, been changed.

In the FIG. 6 arrangement, the nozzle 15 comprises a short, upstream,parallel-sided section 16, leading into a long, divergent, downstreamsection 17. In the FIG. 6 embodiment, the diameter of the upstreamparallel-sided section 16 is 2.3 mm. This section 16 forms the secondconvergence or constriction 18 to gas flow. In the FIG. 6 embodiment,the diameter of the minimum area of the first convergence orconstriction 5 is 1.0 mm, such that the area of the flow cross-sectionof the second convergence 18 is approximately 5.3 times the area of theflow cross-section of the first convergence 5.

The length of the upstream parallel-sided section 16 of the bore of thenozzle 15 is 7 mm. After the upstream parallel-sided section 16, thedivergent downstream section 17 has a cone angle of approximately 8.8°and diverges to provide the bore of the nozzle 15 with a 10 mm exitdiameter at the nozzle's downstream exit 19.

The divergent section 17 is thought to allow the jet issuing from thesonic nozzle 4 to continue to expand supersonically before being brokendown by a series of oblique shocks.

Example of Performance of Second Embodiment

When the syringe of FIG. 6 was fired, with the gas source as a 5 mlcylinder filled with helium at 25 bar, a 1 mg payload of lidocainepowder was successfully distributed over a target area having a diameterof just over 10 mm, approximately equal to the diameter of the nozzle'sdownstream exit 19. The maximum particle penetration was found to beabout 180 μm. Once again, the particle distribution over the target areawas highly uniform. FIG. 7 is top plan view of the agar target. FIG. 8is a magnified cross-section of a diametral slice through the agartarget, showing the penetration of the individual particles. FIG. 9 is areconstruction of a diametral 10 mm wide slice through the agar target,showing the uniformity of distribution and penetration of the particlesacross the full width of the target.

As with the first embodiment, with the second embodiment it is thoughtthat the good distribution of particles across a target areasubstantially equal to the size of the nozzle at the nozzle's downstreamexit is influenced by the relative minimum sizes of the first and secondconvergences 5, 16, the distance by which they are spaced apart and thepositioning of the particle inlet passage 10 relative to the exit of thefirst convergence and the entrance to the second convergence. In thesecond embodiment, it is thought also to be advantageous to have anupstream parallel-sided section 16 ahead of the divergent downstreamsection 17, as it is thought that the parallel-sided section 16 assistsin settling down the gas flow and reattaching to the nozzle walls thediverging gas jet emanating from the first convergence 5.

Clinical Trial Results

A small scale clinical trial was conducted with the first and secondembodiments of the syringe to test their efficacy when deliveringlidocaine to the human skin.

Five volunteers had 1.5 mg of lidocaine administered to their volarforearms. After three minutes, two needle probes were used to comparethe pain experienced at the treated site with that at an untreated siteclose by. All but one of the volunteers found that the needle probes atthe active sites were less painful than those at the non-active sites.Subsequently two volunteers tested lidocaine administrations to thefossa. Both found that the treated sites were completely pain free.

The first embodiment of syringe appeared to be more effective over asmall area of forearm than the second embodiment of syringe used withthe same particle payload. Because, however, the particle penetrationdepth was similar in both cases a likely explanation for this is thatinsufficient lidocaine particles were being administered to the 10 mmdiameter target area with the second embodiment of syringe. FIGS. 10 and11 show the effect of doubling the payload from 1 mg to 2 mg in thesecond embodiment. The penetration depth is slightly reduced to 160 μm(from 180 μm), but the particles are more densely packed.

The second embodiment of syringe was also modified by extending itsnozzle 15 in length. By maintaining the same taper angle of 8.8 degrees,the diameter of the nozzle at its downstream exit 19 was increased to 14mm from 10 mm. This modified arrangement was tested with a 3 mg payloadof lidacaine powder using a 5 ml cylinder of helium at 30 bar. Theresults are shown in FIGS. 12 and 13. Although penetration depth hasagain fallen slightly (to 140 μm), the powder was still found to besubstantially uniformly distributed over the full target area, thetarget area of course this time having a diameter of approximately 14mm.

Third Embodiment

The first and second embodiments described above utilize a firstconvergence or constriction 5 to create a reduced pressure region whichis used to draw in a payload of particles. The first convergence orconstriction as described comprises an upstream constriction 5 a and adownstream constriction 5 b. It is the smaller downstream constriction 5b that is choked during use. The third embodiment relates to amodification of this geometry which replaces the two-stage convergenceof the first and second embodiments with a smoothly tapering convergence5′. As shown in FIG. 14, the convergence 5′ tapers down from a diameterof 6 mm at the upstream end to a diameter of 1.2 mm at the downstreamend over a length of about 17 mm. As with the first and secondembodiments, high pressure gas presented to the upstream end of theconvergence will tend to have its pressure reduced as it flows along thegas flow path through the convergence 5′ and into the chamber 8. Thisreduced pressure can then be used to draw in a payload of particles fromthe particle source 11 (not shown in FIG. 14).

The chamber 8 is the preferred position for the particle inlet passage10 (not shown in FIG. 14) and it has been found that the transsonic gasjet formed effectively entrains the particles such that they areuniformly distributed in the gas flow. However, it is not essential thatthe particles are introduced in this chamber and in fact they may beintroduced at any position in the device where there is a reducedpressure region in the gas flow path. Since the reduced pressure stemsfrom the Venturi effect caused by the first convergence 5′, the deviceis still effective when the particles are introduced upstream of thechamber 8, in the first convergence 5′. It is enough that the gas flowpath has started to converge at the position where the particle inletpassage 10 is located such that there is a reduction in pressuresufficient to draw in the particles. Similarly, the particle inletpassage 10 may be located downstream of the chamber 8 either at thesecond convergence 9 or downstream thereof in the nozzle bore 3. It hasbeen found that the gas pressure in these positions is reduced to avalue sufficient to cause the drawing in effect of the particles.

The third embodiment works in a very similar way to the first and secondembodiments in so far as there is provided a first convergence orconstriction followed by a chamber of increased cross-section followedby another convergence or constriction. The chamber of increasedcross-section is thought to provide a discontinuity to the gas flowwhich leads to the creation within the chamber of a transsonic jet,which jet passes through the chamber and attaches to the walls of thenozzle bore 3 in the region of the second convergence 9. As thetranssonic jet enters the second convergence, a normal shock wave isthought to be formed across the second convergence which increases thepressure and reduces the velocity of the gas. The nozzle portion thenserves to accelerate the particles in the already quickly moving gasstream.

As already mentioned, the first and third embodiments (with a parallelsided nozzle bore 3) are thought to have particular application indentistry where it is useful to achieve penetration of a small targetarea and where the mucosal surfaces are relatively easy to penetrate.This in turn means that low driving pressures can be used (i.e. thepressure presented to the first convergence 5), such as 10 bar forexample. It has been found that the lower the driving pressure, the lessnoise that is created by the device.

In all embodiments, the mass flow rate of gas through the device isdetermined by the driver pressure and the smallest cross sectional flowarea in the device. This smallest area is preferably the firstconvergence 5, 5′. Thus, it is expected that the first convergence willbe choked during normal operation.

Fourth Embodiment

FIG. 15 shows a fourth embodiment of needleless syringe in accordancewith the present invention in which the chamber 8 has been replaced by adivergent section 60. The first convergence or constriction 5′ is shownas having a tapered form similar to that in FIG. 14, although thetwo-stage first convergence 5 a, 5 b of the embodiments of FIGS. 1 and 2would also be acceptable. In this embodiment, because there is nochamber 8, there is no second convergence as such and the gas flow pathdiverges from the point of minimum cross-section of the firstconvergence 5′ to the cross-section of the nozzle bore 3. This change ingeometry means that no transsonic jet is formed and instead theconfiguration acts like a convergent-divergent nozzle which acceleratesthe flow to supersonic speeds (with low static pressures). The particlepayload can be introduced at any point in the gas flow where thepressure is low enough to cause the drawing-in effect to take place. Inpractice this is a position between a point in the convergence 5′ wherethe pressure has reduced enough to a point in the nozzle bore 3 farenough upstream to give the particles adequate residence time in thenozzle to achieve the desired velocity. Thus, the particle inlet passage10 may be positioned anywhere in the divergent section 60.

Fifth Embodiment

In FIGS. 1-2 and 6 the gas source is not shown. As mentioned above, thegas source may advantageously take the form of a single shot gascanister, preferably a helium gas canister. To show one possiblearrangement for this gas canister, FIG. 16 shows a fifth embodiment of asyringe in accordance with the present invention. In this fifthembodiment, the main body 30 is provided with a nozzle 31 having anupstream parallel-sided section 32, a short divergent section 33downstream thereof, followed by a long downstream generally conicalsection 34. Provided on the downstream end of the nozzle 31 is a spacer35, whose downstream face is intended to be placed against the skin ormucosa surrounding the target area to space the nozzle's downstream exitface 36 from the target area. As can be seen the spacer 35 is providedwith a plurality of radial outlets to allow the escape of the drivergas.

As in the first to fourth embodiments, the particle source 37 takes theform of a cassette having a reservoir 38 provided therein to receive thepayload of particles. This reservoir 38 is in communication with theparticle entrainment chamber 39 via the particle inlet passage 40.

Provided at the upstream end of the particle entrainment chamber 39 is asonic nozzle 41, whose central aperture forms the first convergence orconstriction 42 to the flow of gas from the gas source. The secondconvergence or constriction 43 is provided by the upstream end of theupstream parallel-sided section 32 of the bore of the nozzle 31. Theminimum diameters of the first and second convergences shown are 1 mmand 2.3 mm respectively.

The gas source is positioned to the left (as drawn) of the main body 30.The gas source includes a gas cylinder 44 received within a housing 45.The right-hand end (as drawn) of the gas cylinder 44 is provided with alongitudinally extending nose 49, which nose is capable of beingfractured, so as to allow the escape of gas from the interior of thecylinder 44, upon the application of lateral pressure to the nose 45 inthe direction identified by the arrow referenced 46. In the illustratedembodiment, this lateral pressure is applied by moving a plunger 47radially inwardly, using the pressure from a thumb or finger,sufficiently far as to fracture the nose 49 and to cause gas releasefrom the cylinder 44. It is this release of gas which pressurizes thespace upstream of the sonic nozzle 41, leading to choked flow of thereleased gas through the first convergence 42.

The gas cylinder 44 need not have its nose pointed to the right (asdrawn). It may, for example, be turned through 180° so that its nosepoints to the left.

So as to avoid the possibility of any fragments from the fracturing ofthe nose either blocking the sonic nozzle 41, or passing through theaperture provided in the sonic nozzle 41, a thin gauze filter 48 may, asshown, be provided between the gas cylinder 44 and the sonic nozzle 41so as to filter the gas from the cylinder prior to its passage throughthe sonic nozzle 41.

The method and mechanism of operation of the fifth embodiment is similarto that of the first to fourth embodiments and will not be furtherdescribed here.

In all the embodiments, the relationship between the area of the firstand second convergences (or the relationship between the area of thefirst convergence and the area of the nozzle in the fourth embodiment)is thought to be significant. Diameters of 1.0 and 2.3 mm for the firstand second convergences respectively, equating to a flow cross-sectionalarea ratio of 1:5.3 worked well. Other constructions that worked wellwere diameters of 1.2 and 3.0 mm for the first and second convergences,1.3 and 3 mm for the first and second convergences and 1.4 and 3.5 mmfor the first and second convergences respectively, equating to flowcross-sectional area ratios of 1:6.25, 1:5.3 and 1:6.25 respectively. Incontrast, diameters of 1.2 and 2.3 for the first and second convergencesrespectively, equating to a ratio of 1:3.7 did not work well.

For the larger diameter first convergence (e.g. 1.4 mm), a larger massflow rate can be established and a more powerful device can beconstructed. Pressures of up to 60 bar may be used as a driver, in orderto provide enough propellent to support the increased mass flow rate.

In the illustrated embodiments, the particle source 11, whilst suitablefor use in the laboratory, would not be particularly well suited tocommercial use because the powder to be delivered could becomecontaminated and/or fall out of the reservoir provided in the particlesource cassette.

FIG. 17 shows one possible way of sealing a metered quantity of powderin a sealed container until it is ready for use. In FIG. 17 the particlesource 50 has a two-piece construction, comprising a cassette body 51and a rotatable and axially slidable plug 52.

The cassette body 51 has three radial holes 53, 54 provided therein.Hole 54 is a single filling hole to enable the powder cavity 55 in theplug 52 to be filled with a metered dose of powder. A pair ofdiametrically opposed holes 53 are also provided, of which only one isvisible in FIG. 12. One of these holes 53 is a powder exit hole. FIG. 14shows the plug 52 in a position enabling the powder cavity 55 providedtherein to be filled through the filling hole 54. After filling, theplug 52 is slid to the left (as drawn) to position the powder cavity 55in the same plane as holes 53, but not to align it with either of holes53. The cassette 50 can then be mounted on the syringe with one or otherof its radial throughholes 53 aligned with the syringe's particle inletpassage leading to the particle entrainment chamber 8. To prime thecassette prior to use a tool, for example a screwdriver type blade, canbe inserted into a slot 57 provided in the right-hand end (as drawn) ofthe plug, enabling the plug to be rotated through 90° within thecassette body 51 to bring the powder cavity 55 into alignment with bothof the diametrically opposed holes 53. By priming the cassette in thisway, when the syringe is then operated, air can enter through theupstream one of the pair of holes 53, enabling the powder in the cavity55 to be carried out of the other of the pair of holes 53, through theparticle inlet passage, into the particle entrainment chamber.

FIGS. 18 a to 18 f show a second way of sealing a metered quantity ofpowder in a sealed container until it is ready for use. The samereference numerals as FIG. 17 are used where possible. FIG. 18 a shows aplug member 52, FIGS. 18 b and 18 c show orthogonal views of a cassettebody 50 and FIGS. 18 d to 18 f show the plug member 52 inserted into thecassette body 50 in various orientations. As in FIG. 17, the cassettebody 50 has three radial holes 53, 54 provided therein, a single fillinghole 54, to enable the powder cavity 55 in the plug 52 to be filled witha metered dose of powder and a pair of diametrically opposed holes 53which are used when the plug 52 is in the operating position (FIG. 18f). As with the FIG. 17 embodiment, the plug 52 is rotatable in thecassette body but, contrary to the FIG. 17 embodiment, is not meant tobe actively slidable in use. Before filling, the plug 52 is aligned withfilling hole 54 so that particles can be placed in the powder cavity 55via hole 54 (see FIG. 18 d). The plug 52 is then rotated (again by usinga screwdriver in slot 57 or other means for turning, e.g. using aspanner or manually operating a lever built into the plug 52) byapproximately 45° such that, although the powder cavity 55 is in thesame plane as all three of the holes 53, 54, it is not in communicationwith any of them (see FIG. 18 e). This storage position ensures that thepowder cannot escape. In use, the plug 52 is rotated by a further 45° sothat the particles come into fluid communication with each of thediametrically opposed holes 53 (see FIG. 18 f). Thus, although similarto the FIG. 17 embodiment, this embodiment does not require theadditional step of actively sliding the plug 52.

FIG. 19 shows the cassette body 50 and plug 52 mounted on a needlelesssyringe similar to that shown in FIG. 1. As can be seen, the cassettebody 50 can be made integral with the syringe main body 1 so that theholes 53 are aligned with the particle inlet passage 10 and theatmosphere respectively.

It will be appreciated that there will be numerous other possible waysfor hermetically sealing a pre-measured dose of powder prior to use ofthe syringe.

Exit Nozzle Configurations

Various configurations of exit nozzle have been found to be effective.FIGS. 1 and 19 show an exit nozzle 2 having a substantially parallelsided bore 3. This can be used to deliver particles to a relativelysmall target area, and due to the localized delivery has been found tobe particularly effective in dental applications for example inanesthesia. FIGS. 6 and 20 show an exit nozzle 2 having a relativelyshort parallel section 16 followed by a divergent section 17. This hasbeen found to effectively increase the target area of particlepenetration, although there seems to be a limit as to how much the exitnozzle can diverge before boundary layer separation takes place and thejet forms a “core” of particles which is smaller than the exit diameterof the nozzle.

To address this problem of “coring”, the nozzle shown in FIG. 21 hasbeen developed in which a short parallel section 16 is followed by adivergent section 17 which in turn is followed by a parallel section 65.The downstream parallel section 65 following the divergent section 17helps to reattach the boundary layer which can become separated in thedivergent section 17 and yields a more uniform particle distributionacross the whole exit diameter of the nozzle.

Sixth Embodiment

FIG. 22 shows a sixth embodiment of the invention which combines many ofThe features of the previously described embodiments but also has anovel actuating Mechanism which serves to align the powder cassette plug52 into the operating position and Actuates the cylinder fracturingmechanism in one simple operation. As can be seen from FIG. 22, anactuating lever 66 is provided which rotates about the same pivot axis(not shown) as the plug 52 of the powder cassette. Initially, theactuating lever 66 is provided in a primed position in which the powdercavity 55 is oriented at 45° from the position in which it is alignedwith the particle inlet passage 10. This is the previously described“storage” position. The actuating lever 66 can be pressed by the thumbof an operator and in so doing rotates about its pivot axis to bring thepowder cavity 55 almost into alignment with the diametrically opposedholes and thus bring the powder into fluid communication with the gasflow path (via the particle inlet passage 10). This position ofactuating lever is also shown in FIG. 22 and is denoted by 66′. In thefinal stages of pressing the actuating lever 66, the lever 66 abuts theactuating pin 47 and further pressure causes the frangible tip 49 of thegas cylinder 44 to fracture and thereby triggers the device (FIG. 22shows the frangible tip 49 in both an unbroken and broken position). Thelever 66 typically turns 40° before it abuts the actuating pin 47 andthe final 5° is used to fracture the cannister tip and bring the powdercavity 55 into full alignment. Thus, a mechanism is provided whereby thepowder can be moved from the storage position to the operating positionand the device can be triggered in one easy movement.

FIG. 22 is shown with the nozzle of FIG. 21 (parallel-divergent-parallelnozzle). However, any of the heretofore described nozzle designs maybeutilized, either with or without a spacer 35.

Seventh Embodiment

The above embodiments all utilize a first convergence 5, 5′ to create areduced pressure region which can be used to draw the particles into thegas flow path. In the embodiments shown, since the particles areinitially provided in contact with the atmosphere, the reduced pressuremust necessarily be sub-atmospheric for the effect to work properly. Theseventh embodiment relates to a construction in which the particles areprovided in fluid communication with an upstream portion of the gas flowpath such that, in use, the reduced pressure need not be sub-atmosphericand need only be reduced compared to the pressure at that upstreamportion of the flow path.

FIG. 23 schematically illustrates the concept on a device having asimilar construction to that shown in FIG. 14, but with a divergentnozzle. In FIG. 25, the powder cassette 50 is rotated 90° about avertical axis as compared with the orientation shown in FIGS. 19 to 22,and the top hole 53 of the powder cassette 50, instead of being ventedto atmosphere, is provided in fluid communication with an upstream part68 of the gas flow path, upstream of the first convergence 5′. Thisfluid communication is achieved by passage 69. The particle inletpassage 10 fluidly communicates with the other hole 53 of the particlecassette 50 and a more downstream part 70 of the convergence 51. Theconvergence 5′ causes a reduction in gas pressure, in use, due to theVenturi effect such that there is, in use, a pressure differentialacross the powder cavity 55. Thus, even if the pressure in the gas flowpath at a position 70 adjacent the particle inlet passage 10 is notsub-atmospheric, the particles are still drawn into the gas flow pathbecause the pressure is at least reduced compared to the pressure towhich the particles are exposed (i.e. that pressure present at theupstream end 68 of the device).

The amount of gas which flows along the passage 69 is preferably smallcompared to the flow rate along the gas flow path, e.g. 20% or so.

Theoretically, gas pressure close to the driver pressure can be used toinject the particles into the gas flow. Typically, though, the particleinlet passage 10 and passage 69 are positioned so that about 0.2 timesthe driver pressure is present across the particles in use. When 30 bardriver pressure is used, this corresponds to a pressure difference of 6bar which serves to draw the particles into the flow. By modifying thispressure difference, the time at which the particles are drawn into theflow can be controlled. This timing can also be controlled by modifyingthe length and/or tortuousness of the passage 69.

Thus, this embodiment provides a form of particle “injection” and givesgreater flexibility as to where the particles can be introduced sincethe requirement for sub-atmospheric pressure is dispensed with. Althoughthe particles are shown being injected into the first convergence 5′,they may be injected into the chamber 8, the second convergence 9, thenozzle bore 3, 16, 17 or the divergent section 60 as described inrelation to the other embodiments.

This embodiment has the further advantage that no atmospheric air isinduced into the gas flow meaning that the device is self-contained inuse. This reduces the possibility of contamination of the particles bycontaminants suspended in atmospheric air.

Eighth Embodiment

As described above, a large divergent portion 17 of the exit nozzle 2can cause “coring” whereby the boundary layer separates from the nozzlewalls and the majority of the jet power is concentrated along a centrallongitudinal axis such that the particles are not evenly distributedacross the full area of the nozzle at the nozzle exit plane. This can beameliorated by the use of a second parallel section 65 (see FIG. 21) andit is thought the parallel section 65 encourages re-attachment of theboundary layer in the nozzle. However, it is desirable to prevent theinitial detachment to provide a more desirable gas flow from the pointof view of good particle injection. The eighth embodiment provides afurther modification to the divergent section 17 of the exit nozzlewhich can ameliorate this effect.

FIG. 24 schematically shows the principle as applied to the embodimentof FIG. 14, but with a divergent nozzle. A return gas flow path 71 isprovided between a point 72 in the divergent nozzle and a point 73upstream of that point 72. The Venturi effect means that the position 73of lower cross-sectional area will have a reduced pressure as comparedto the position 72 of higher cross-sectional area. This will cause gasflow to be routed from the downstream point 72 to the upstream point 73due to the pressure differential in use. This creates a suction effectnear the walls of the nozzle at the downstream point 72 which tends todelay separation of the boundary layer from the walls. This embodimentcan therefore be utilized to provide a more even spread of particles andless “coring” of the gas stream.

Ninth Embodiment

This embodiment utilizes a further nozzle geometry which is similar tothe geometry shown in FIG. 21 except that the divergence extends over avery short length longitudinally, as shown in FIG. 25. The divergencetypically covers a longitudinal length “A” of only one quarter to oneeighth of the diameter of the second convergence 9 and this nozzlegeometry is referred to as a “fast expand” nozzle. The idea behind it isthat the gas should be expanded as quickly as possible so as to ensurethat particles are accelerated by the fast moving gas stream for thelongest time period possible. This is thought to provide a higherparticle speed. The “fast expand” nozzle may be used to replace thenozzle of any of the previously described embodiments.

Examples of Performance of Some Embodiments

The device shown in FIG. 20 having a 10 mm nozzle exit diameter has beentested with different volumes (3 and 5 ml) and driver pressures (20 to60 bar). In general, low driving pressures (5 ml at 25 bar) give veryuniform distribution of the particles on the target but with relativelylow penetrations (160 to 180 μm) of 47 μm diameter polystyrene beadsinto a 3% agar gel target. As the driver pressure is increased, thepenetration increases but the particle distribution becomes more skewedto that side of the target which is opposite the position of powderentry via the particle inlet passage 10. Further increase of the gaspressure causes the pressure in the chamber 8 to rise above that of theatmosphere which results in the particles being ejected from the airaspiration hole. This problem was overcome by increasing the diameter ofthe upstream parallel exit nozzle section to accommodate the higher gasflow rates.

Mass flow rates (and particle penetration) were also increased by usinglarger diameter sonic throats. In this embodiment, which utilizes theoutside atmospheric pressure to draw in the particle payload, it isnecessary to ensure that the sonic throat and parallel section of thediameters are matched, to prevent a blow-back of particles. Thealignment of the sonic throat exit plane and the particle inlet passage10 in the chamber 8 is also important in preventing the particleblow-back.

A 10 mm diameter exit plane device, fitted with a 1.2 mm diameter sonicthroat and a 3 mm diameter upstream exit nozzle parallel section andusing a 5 ml, 40 bar helium cannister gave the footprint and penetrationresults shown in FIG. 26. The payload was 1 mg of 48 μm of polystyrenebeads.

The left hand image shows the footprint (approximately 11 mm diameter)of the particles and a 3% agar gel target: there is an increasedconcentration of particles near the centre of the footprint, but theasymmetry of the distribution is not so noticeable in this image. Themiddle image shows the distribution of particles across a diametralslice of the target and the left hand image shows an enlarged view ofparticle penetration at the center of the slice, from which a maximumpenetration of 250 μm can be measured.

Noise levels from this device at these conditions were not high (max=81dBA, linear peak=120 dB, measured at 0.3 meters).

A simple silencer device (shown in FIG. 27) was fitted to the FIG. 20embodiment. The silencer consists of a first passage 80 which the gasupon which rebounding from the target plane passes along. This passage80 is aligned in an annulus around the exit nozzle 17. The gas thenpasses through a port 81 before being passed across a series of radiallyextending baffles 82. It is thought the baffles serve to breakdown thegas pressure into a series of shock waves. Finally, the gas passesthrough a mesh filter 83 and out through an exit port 84.

This arrangement produced significantly lower noise levels (max=73 dBA,linear peak=109 dB at 0.3 meters). Use of the silencer produces a backpressure which has two effects. The first effect is to generate a“lift-off” force which tends to separate the device from the targetplane and the second effect is to reduce the performance of the device,since the gas is now expanded to a nozzle exit pressure aboveatmospheric.

The lift-off force of the silenced device was measured by operating itagainst a flat plate loaded with different masses, a displacementtransducer indicating when the sealing force was insufficient tomaintain contact. This method gave lift-off forces of the order of 5 N,which is considerably lower than the Fig. obtained by assuming that thepeak pressure maintained on the plate generates the maximum lift-offforce (13 N).

FIG. 28 shows the same data for the silenced device as that displayed inFIG. 26 for the unsilenced device. The main difference is that themaximum penetration has been reduced to 225 μm.

The device shown in FIG. 21 was also tested. This device also has a 10mm diameter exit plane and the downstream parallel extension 65 is 30 mmlong.

FIG. 29 shows the improved footprint achieved when this device wasoperated at conditions corresponding to those of FIG. 26. The particlesare more uniformly dispersed over the target and the maximum penetrationis still 250 μm. The measured noise levels in this case were max=79.3dBA, linear peak=119.4 dB. The device of FIG. 20 was also tested with a0.6 mg payload of 50 R gold particles (mean diameter=1.8 μm). The sonicthroat was increased to 1.3 mm and used with a 50 bar, 5 ml heliumcylinder. The footprint and mean penetrations are shown in FIG. 30.

It can be seen from the Figures that the particles are fairlyasymmetrically distributed on the target and that the distribution ofpenetration depths is large—ranging from 60 μm at the edges to 120 μmnear the center.

A 30 mm parallel extension as shown in FIG. 21 was added to the deviceand the results are shown in FIG. 31. As can be seen, matters were notparticularly improved since the mean penetration depths are now lower,the asymmetric distribution is still evident and the variation in depthof the particles has increased.

An improved distribution and penetration was achieved by adding goldparticles to larger diameter lidocaine powder in the powder cassette.The gold particles were sandwiched between two layers of lidocaine. Theresults are shown in FIG. 32 where it can be seen that the lidocaineparticles caused some damage to surface of the agar gel target, butdissolved rapidly to leave the gold particles behind.

The most powerful version of the FIG. 20 device tested had a 1.4 mmdiameter sonic throat, a 3.5 mm diameter upstream exit nozzle sectionand used a 60 bar, 5 ml helium cannister. When used with a payload of 1mg of polystyrene spheres, it produced a crater in the centre of the 3%agar gel target. With the 30 mm parallel extension (FIG. 21) there wascomparatively little damage to the target. An example of the performanceof the device is shown in FIG. 33 where the target is a 3% agar gel andthe payload was 1 mg of 50 μm agarose beads (A-121). These particleshave a lower density than either polystyrene or lidocaine andconsequently they do not penetrate as deeply for a given velocity.Nevertheless, the maximum penetration measured was 280 μm.

FIG. 34 shows the results when the device of FIG. 20 was used with a 1mg payload of particles and a driver pressure of 25 bar. As can be seen,a maximum penetration of 120 μm and a footprint of about 11 mm diameterwas obtained.

It may be advantageous to provide a high efficiency particle air filterso as to remove any potential source of contamination from air drawninto the syringe through the cassette of the particle source. Suchfilters are commercially available and have low pressure drops. Suchfilters have an upper limit to gas velocity through the filter so as toensure that they operate to the specification. The surface area of sucha filter could clearly be chosen to match the gas velocity therethroughthat will be encountered in use.

An alternative to an air filter would be to bleed a supply of driver gasat, or near, atmospheric pressure to the particle cassette inlet. Asdescribed above with relation to the seventh embodiment, however, thegas bled to the particle inlet may be substantially higher thanatmospheric.

Although the above described embodiments were used for single doseoperation, they may readily be modified to make them suitable formultiple dose operation, for example by providing them with a pluralityof gas canisters and modifying the cassette of the particle source 11 tocontain a plurality of discrete particle reservoirs 12, each of whichcan be indexed to align with the particle inlet passage 10 betweensuccessive shots.

Any of the already described nozzles may be contoured, for example,using the method of characteristics, to provide a reduction in thenumber of oblique shock waves that form in the nozzle during use.Profiling the nozzle in this way is also thought to improve the particledistribution at the exit plane.

For some use locations, such as surgeries, operating theaters and thelike, in which connection of the syringe to a supply of gas using aflexible hose, for example, would be acceptable, multiple operation ofthe device could well be possible using a simple push-pull valvearrangement to fire the syringe.

The major components of the needleless syringe (main housing, sonicnozzle, nozzle barrel etc) may for example be made of metal or ofengineering plastics materials. The latter materials are preferredbecause they may readily be molded and are light in weight.

Although the device of all embodiments of the present invention isdesigned to be quieter in operation than the device of U.S. Pat. No.5,630,796 (which uses a rupturable membrane), some noise is stilldetected and a silencing device, perhaps comprising a plurality ofbaffles and a mesh filter can be used to further reduce the noiseexperienced.

The present invention is primarily concerned with the reduction of noiseand improved uniform particle spread that can be achieved by using theVenturi effect to draw the particles into the gas flow path. However,the Venturi effect is not essential for this purpose and other methodsof introducing the particles into the flow may be utilized. For example,the particles may be initially lightly adhered to the inside of atubular member which is initially provided in the gas flow path. Uponactuation, the gas flow is able to shear the particles from the tube andthereby entrain them.

1. A needleless syringe for use in the needleless injection of particlesinto the skin of a vertebrate subject, the syringe comprising: a gasflow path arranged to receive gas from a gas source; a first convergencein said gas flow path for reducing the pressure of the gas flowingthrough said gas flow path; a particle inlet for introducing particlesinto said gas flow separately from the gas, said particle inlet being incommunication with said gas flow path downstream of at least the startof said first convergence so as to allow a payload of particles to bedrawn into the gas flow path via the particle inlet under the action ofreduced pressure gas to become entrained in the gas; a gas/particle exitnozzle bounding said gas flow path for the acceleration of the drawn inparticles entrained in the gas; and a powder chamber, containing atleast one payload of particles, in communication with the particle inletso as to enable the particles of a payload to be drawn into the gas flowpath from said powder chamber along the passage of said particle inlet,wherein said powder chamber is configured to be moved so as to bringsaid particle payload into and out of communication with said particleinlet.
 2. A syringe according to claim 1, further comprising a chamberof increased cross-section downstream of said convergence and boundingsaid gas flow path such that, in use, a transsonic gas jet is formed insaid chamber.
 3. A syringe according to claim 2, wherein said particleinlet is positioned relative to said chamber so that the particles aredrawn, in use, into the chamber.
 4. A syringe according to claim 3,wherein the nozzle is provided at its upstream end with a gas andparticle inlet for the flow therethrough into the nozzle of the drawn-inparticles entrained in the gas jet, said gas and particle inletcomprising a second convergence of reduced flow cross-section relativeto the flow cross-section of the chamber.
 5. A syringe according toclaim 4, wherein the minimum flow cross-section of the secondconvergence is at least 4 times the area of the minimum flowcross-section of the first convergence.
 6. A syringe according to claim4, wherein the first and second convergences are aligned along a commonaxis and the particle inlet comprises a passage whose centrallongitudinal axis is generally transverse to said common axis.
 7. Asyringe according to claim 1, wherein said gas flow path comprises adivergent section downstream of said convergence.
 8. A syringe accordingto claim 7, wherein said particle inlet is positioned in said divergentsection.
 9. A syringe according to claim 6, wherein said particle inletis positioned in said exit nozzle.
 10. A syringe according to claim 1,wherein said particle inlet is positioned in said first convergence. 11.A syringe according to claim 1, wherein moving said powder chamber sothat said particle payload is in communication with said particle inletalso triggers said syringe.
 12. A syringe according to claim 1, whereinsaid particle inlet is connected or connectable to an upstream region ofthe gas flow path such that the particles will, in use, be drawn intothe gas flow path due to the pressure difference between said upstreamregion and the gas flow path adjacent the particle inlet.
 13. A syringeaccording to claim 1, wherein the exit nozzle comprises an upstream,parallel-sided section, leading into a divergent section.
 14. A syringeaccording to claim 13, further comprising a passage fluidly connecting apart of said divergent section with a more upstream part of the gas flowpath.
 15. A syringe as claimed in claim 13, wherein the diameter of thenozzle at its downstream exit is between 2 and 30 mm in diameter.
 16. Asyringe according to claim 4, wherein said second convergence is anabrupt constriction.
 17. A syringe according to claim 1, wherein saidfirst convergence is an abrupt constriction.
 18. A syringe according toclaim 4, wherein the minimum flow cross-section of the secondconvergence is at least 5 times the area of the minimum flowcross-section of the first convergence.
 19. A syringe as claimed inclaim 13, wherein the diameter of the nozzle at its downstream exit isbetween 3 and 15 mm.
 20. A syringe as claimed in claim 13, wherein thediameter of the nozzle at its downstream exit is greater than 5 mm. 21.A syringe as claimed in claim 13, wherein the diameter of the nozzle atits downstream exit is greater than 8 mm.
 22. A syringe as claimed inclaim 13, wherein the diameter of the nozzle at its downstream exit isgreater than 11 mm.
 23. A syringe as claimed in claim 1, furthercomprising a source of compressed gas connected to the upstream end ofsaid gas flow path.